Processes for preparation of polymorphic form II of sertraline hydrochloride

ABSTRACT

Provided are processes for preparation of crystalline sertraline hydrochloride Form II substantilly free of other polymorphic forms of sertraline hydrochloride, preferably on an industrial scale.

CROSS REFERENCE TO RELATED APPLICATION

This application claims the benefit under 35 U.S.C. §119(e) ofprovisional application Ser. No. 60/376,787, filed Apr. 29, 2002 whichis incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to the solid state chemistry of sertralinehydrochloride.

BACKGROUND OF THE INVENTION

Sertraline hydrochloride, (1S-cis)-4-(3,4 dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine hydrochloride, having theformula:

is approved, under the trademark Zoloft®, by the U.S. Food and DrugAdministration, as a serotonin re-uptake inhibitor for the treatment ofdepression, obsessive-compulsive disorder, panic disorder andpost-traumatic disorder. In the solid state, sertraline hydrochlorideexists in various crystalline forms having different physicalproperties.

The present invention relates to the solid state physical properties,i.e., polymorphism, of sertraline hydrochloride. These properties may beinfluenced by controlling the conditions under which sertralinehydrochloride is obtained in solid form. Solid state physical propertiesinclude, for example, the flowability of the milled solid. Flowabilityaffects the ease with which the material is handled during processinginto a pharmaceutical product. When particles of the powdered compounddo not flow past each other easily, a formulation specialist must takethat fact into account when developing a tablet or capsule formulation,which may necessitate the use of glidants such as colloidal silicondioxide, talc, starch or tribasic calcium phosphate.

Another important solid state property of a pharmaceutical compound isits rate of dissolution in aqueous fluid. The rate of dissolution of anactive ingredient in a patient's stomach fluid may have therapeuticconsequences because it imposes an upper limit on the rate at which anorally-administered active ingredient may reach the bloodstream. Therate of dissolution is also a consideration in formulating syrups,elixirs and other liquid medicaments. The solid state form of a compoundmay also affect its behavior on compaction and its storage stability.

These practical physical characteristics are influenced by theconformation and orientation of molecules in the unit cell, whichdefines a particular polymorphic form of a substance. The polymorphicform may give rise to thermal behavior different from that of theamorphous material or another polymorphic form. Thermal behavior ismeasured in the laboratory by such techniques as capillary meltingpoint, thermogravimetric analysis (TGA) and differential scanningcalorimetry (DSC), and may be used to distinguish some polymorphic formsfrom others. A particular polymorphic form may also give rise todistinct properties that may be detectable by powder X-ray diffraction,solid state ¹³C NMR spectrometry and infrared spectrometry.

A solid form (polymorph) of sertraline hydrochloride is disclosed forexample in WO 01/90049, which is directed to amorphous form ofsertraline hydrochloride. The solid state chemistry of sertralinehydrochloride is also disclosed in JP 0026378 and JP 0026379. Accordingto the English abstract of JP 0026379, “a sertraline free base isdissolved in a solvent (e.g. an ester-based organic solvent such asethyl acetate, butyl acetate or the like or a ketone-based organicsolvent such as acetone, methyl isobutyl ketone or the like) or asertraline organic acid salt is suspended in a solvent, and hydrochloricacid or hydrogen chloride is introduced into the solution or suspensionpreferably at a room temperature or the reflux temperature of thesolvent to give sertraline hydrochloride crystal of metastable form ofthe formula. The sertraline free base is obtained, for example, by amethod for decomposing sertraline mandelate with an alkali. The amountof the hydrochloric acid or hydrogen chloride used is preferably 1.0-5.0mol based on 1.0 mol of the sertraline free base or the organic salt.”

U.S. Pat. No. 4,536,518, incorporated herein by reference, describes asynthesis of sertraline hydrochloride. U.S. Pat. No. 5,248,699,incorporated herein by reference, describes five crystalline forms ofsertraline hydrochloride, designated Form I, Form II, Form III, Form IVand Form V. These and additional forms of sertraline hydrochloride arealso disclosed in U.S. Pat. Nos. 6,452,054, 6,495,721 and 6,500,987,incorporated herein by reference.

U.S. Pat. No. 4,536,518 (“the '518 patent”) describes the preparation ofsertraline hydrochloride with a melting point of 243-245° C. by treatingan ethyl acetate/ether solution of the free base with gaseous hydrogenchloride. The solid state properties of the sertraline hydrochloride soproduced are not otherwise disclosed.

According to U.S. Pat. No. 5,248,699 (“the '699 patent”), the sertralinehydrochloride produced by the method of the '518 patent has acrystalline form denominated “Form II”. The method described in the '699patent for making Forms II and IV is by the rapid crystallization ofsertraline hydrochloride from an organic solvent. An actual example isnot provided.

The '699 patent discloses that Forms II, III, IV and V are metastable,and that granulation of Forms II, III or IV in isopropyl alcohol, ethylacetate, hexane at a temperature of 40° to 60° C. causes conversion toForm I.

The preparation of sertraline hydrochloride Form II is also disclosed inWO 01/32601. In Examples 9-12, sertraline hydrochloride Form II isprepared from a maximum of 50 grams of sertraline free base in solution.The specification further discloses regarding Form II: “Sertralinehydrochloride polymorphic form II may be formed from a solution ofsertraline free amine with some seeding crystals of form II before theaddition of a solution of hydrogen chloride; or from a stirredsuspension of sertraline hydrochloride polymorphic form V with someseeding crystals of sertraline hydrochloride polymorphic form II; or bydrying a sertraline hydrochloride alcohol solvate at temperatures fromabout 0 to 30° C. in high vacuum (<1 mbar); or from stirred suspensionsof sertraline hydrochloride polymorphic form CSC1, CSC2 or T1 with someseeding crystals of sertraline hydrochloride polymorphic form II.Furthermore, Sertraline hydrochloride polymorphic form II may be formedaccording to a process, wherein a solution of sertraline free amine isseeded with some crystals of polymorphic form II and a solution ofhydrogen chloride is added.”

WO 02/096859, also discloses processes for preparation of sertralinehydrochloride Form II. In the examples, sertraline hydrochloride isprepared from a maximum of 40 grams of sertraline mandelate salt; afterobtaining a solution of the free base in isopropanol, hydrogen chloridein ethyl acetate is added at a controlled rate to obtain thehydrochloride salt.

There is a need in the art for preparation of sertraline hydrochlorideForm II substantially free of other polymorphic forms of sertralinehydrochloride, particularly on an industrial scale.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides a reproducible process forpreparation of sertraline hydrochloride Form II substantially free ofcrystalline sertraline hydrochloride Form I comprising the steps ofproviding a solution of sertraline base, or a solution or slurry ofsertraline mandelate, in an organic solvent, contacting the solution orthe slurry with a flow of gaseous hydrogen chloride at a suitable rateat a temperature within the range of from about 30° C. to about 60° C.,during which time sertraline hydrochloride Form II forms, wherein thetemperature is kept substantially constant during the gas flow, andfiltering the sertraline hydrochloride Form II at a temperature of fromabout 30° C. to about 60° C. to obtain sertraline hydrochloride Form IIsubstantially free of sertraline hydrochloride Form I.

In another aspect, the present invention provides a reproducible processfor preparation of sertraline hydrochloride Form II substantially freeof sertraline hydrochloride Form I on an industrial scale comprising thesteps of contacting a solution of sertraline base or a solution orslurry of sertraline mandelate in an organic solvent at a temperaturewithin the range of about 30° C. to about 60° C. with a flow of gaseoushydrogen chloride to form sertraline hydrochloride Form II, andfiltering the sertraline hydrochloride at a suitable temperature toobtain sertraline hydrochloride Form II containing less than about 1%sertraline hydrochloride Form I (wt/wt sertraline hydrochloride),wherein the temperature is kept substantially constant during the gasflow.

In another aspect, the present invention provides for a reproducibleprocess for preparing sertraline hydrochloride Form II substantiallyfree of sertraline hydrochloride Form I on an industrial scalecomprising contacting a solution of sertraline base in a C₃ to a C₄alcohol at a temperature within the range of from about 30° C. to about60° C. with a flow of gaseous hydrogen chloride for about ½ hour toabout 2 hours to obtain a slurry of sertraline hydrochloride, andfiltering the slurry to obtain a sertraline hydrochloride Form II withless than about 1% sertraline hydrochloride Form I (wt/wt sertralinehydrochloride Form I/sertraline hydrochloride), wherein the temperatureis kept substantially constant during the gas flow and the filteringsteps.

In another aspect, the present invention provides for an industrialscale sized batch of crystalline sertraline hydrochloride Form II forpreparation of a pharmaceutical oral dosage form of sertralinehydrochloride on an industrial scale, wherein the batch does notsubstantially convert to sertraline hydrochloride Form I when exposed toa temperature of about 40° C. and a relative humidity of about 75% forat least about 2 months. Preferably the conversion is less than about 1%weight of sertraline hydrochloride Form I to sertraline hydrochloride,more preferably the conversion is less than about 0.5% weight ofsertraline hydrochloride Form I to sertraline hydrochloride, and mostpreferably the conversion is less than about 0.1% weight of sertralinehydrochloride Form I to sertraline hydrochloride. Preferably, the batchsize is at least about 1 Kg, more preferably at least about 10 Kg.(measured after drying for a few hours at elevated temperature, such asthat carried out in Example 5).

In another aspect, the present invention provides for an oralpharmaceutical dosage form prepared from an industrial scale sized batchof crystalline sertraline hydrochloride Form II, wherein the sertralinehydrochloride Form II in the oral pharmaceutical dosage form does notsubstantially convert over time to Form I when exposed to a temperatureof about 40° C. and a relative humidity of about 75%. Preferably, theconversion is less than about 5% weight of sertraline hydrochloride FormI to sertraline hydrochloride after at least about 6 months of storage,more preferably the conversion is less than about 1% weight ofsertraline hydrochloride Form I to sertraline hydrochloride after atleast about 3 months of storage, and most preferably the conversion isless than about 1% weight of sertraline hydrochloride Form I tosertraline hydrochloride after at least about 1 month of storage.

In another aspect, the present invention provides for an industrialscale sized batch of crystalline sertraline hydrochloride Form II forpreparation of a pharmaceutical oral dosage form of sertralinehydrochloride, wherein the batch is substantially free of sertralinehydrochloride Form I as an impurity. Preferably, the impurity is lessthan about 1% weight sertraline hydrochloride Form I as a wt/wtpercentage to sertraline hydrochloride, more preferably the impurity isless than about 0.5%, and most preferably the impurity is less thanabout 0.1%.

In another aspect, the present invention provides for a tablet comprisedof sertraline hydrochloride and the following excipients, in weight toweight percentages, wherein the tablet is prepared from an industrialsized batch of sertraline hydrochloride Form II substantially free ofsertraline hydrochloride Form I: about 20% to about 35% sertralinehydrochloride Form II, about 25% to about 40% lactose monohydrate, about5% to about 12% croscarmellose sodium NF, about 1% to about 3% povidone,about 20% to about 40% microcrystalline cellulose and about 0.5% toabout 2.5% magnesium stearate; and methods of administration to inhibitserotonin re-uptake.

In another aspect, the present invention provides for an industrialscale sized batch of sertraline hydrochloride Form II prepared by areproducible process on an industrial scale free of XRPD peaks at 14.1,15.0, 15.3, 15.7, 21.2 and 26.3±0.2 degrees two theta.

In another aspect, the present invention provides an industrial sizedbatch of crystalline sertraline hydrochloride characterized by an X-raypowder diffraction pattern with peaks at 5.4, 10.8, 14.6, 16.3, 18.1,19.0, 20.3, 21.8, 24.4 and 27.3±0.2 degrees two theta, with the saidpattern being free of peaks between the region 15.0 to 16.0 degrees twotheta, i.e., having substantially the 15.0 to 16.0 degrees two thetaregion depicted in FIG. 1. Preferably, the pattern is free of peaks at15.0, 15.3 and 15.7±0.2 degrees two theta, more preferably also free ofpeaks at 21.2 and 26.3±0.2 degrees two theta, and most preferably alsofree of a peak at 14.1±0.2 degrees two theta.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an x-ray powder diffraction pattern of sertralinehydrochloride Form II substantially free of sertraline hydrochlorideForm I.

FIG. 2 is an x-ray powder diffraction pattern of sertralinehydrochloride Form I.

FIG. 3 is an x-ray powder diffraction pattern comparing the pattern ofsertraline hydrochloride Form I, Form II and Form II containing about 2%Form I.

DETAILED DESCRIPTION OF THE INVENTION

Percentages of sertraline hydrochloride Form I and Form II are inrespect to all forms of sertraline hydrochloride combined.

The present invention provides a pure and/or stable crystallinesertraline hydrochloride Form II in a batch and pharmaceuticalformulations prepared from such batch, and reproducible processes forsuch batch, preferably on an industrial scale. The term “batch”, whichis used to refer to a pharmaceutical bulk preparation, preferably on anindustrial scale, such as that illustrated in Example 5, means “Aspecific quantity of a drug of uniform specified quality producedaccording to a single manufacturing order during the same cycle ofmanufacture.” (Ansel, H et al., Pharmaceutical Dosage Forms and DrugDelivery Systems, 7^(th) Ed., Page 144). The term “pure” meanssertraline hydrochloride Form II substantially free of sertralinehydrochloride Form I. The term “reproducible process” means a processthat produces a product of a specified quality on a consistent basis.

The batch size for industrial scale is preferably at least about 0.5 Kg,more preferably at least about 1 Kg (10 liter batch volume), and mostpreferably at least about 10 Kg (100 liter batch volume). Example 5illustrates such an industrial process, which prepares sertralinehydrochloride in a batch having about 20 Kg of sertraline hydrochloride.

The batch of crystalline sertraline hydrochloride Form II prepared issubstantially free of other crystalline forms of sertralinehydrochloride, particularly crystalline Form I of sertralinehydrochloride. The batch of the pure sertraline hydrochloride Form IIpreferably has a level of Form I of less than about 1%, more preferrablyless than about 0.5% and most preferrably less than about 0.1% w/w (% ofsertraline hydrochloride Form I/sertraline hydrochloride). FIG. 1 is anX-Ray powder diffraction (“XRPD”) pattern which substantially depictssuch pure sample of sertraline hydrochloride Form II.

A suitable method for determining the presence of crystal Form I ofsertraline hydrochloride in sertraline hydrochloride crystal Form II isanalysis of an XRPD pattern. The XRPD pattern of sertralinehydrochloride From I (FIG. 2) is characterized by peaks at 7.1, 12.7,14.1, 15.0, 15.3, 15.7, 20.9, 21.2,23.5 and 26.3±0.2 degrees two theta.The XRPD of pure sertraline hydrochloride Form II (FIG. 1) ischaracterized by peaks at 5.4, 10.8, 14.6, 16.3, 18.1, 19.0, 20.3, 21.8,24.4 and 27.3±0.2 degrees two theta.

Determination of presence of sertraline hydrochloride Form I insertraline hydrochloride Form II may be made by analysis for thepresence of various peaks associated with Form I, particularly at 14.1,20.9, 21.2 and 26.3±0.2 degrees two theta and the region 15-16 degreestwo theta. Preferred peaks for detection include 15.0, 15.3, 15.7, 21.2and 26.3±0.2 degrees two theta. Under routine analytical conditions thelevel of detection of sertraline hydrochloride Form I in sertralinehydrochloride Form II is about 0.1% wt/wt.

The industrial sized batch of sertraline hydrochloride Form II of thepresent invention preferably does not substantially convert over time toForm I, preferably before formulation, upon storage at about 40° C. andabout 75% relative humidity. The conversion does not occur for at leastabout 1-2 weeks, more preferably for at least about 1-2 months, and mostpreferably for at least about 3-4 months, into sertraline hydrochlorideForm I. The conversion is preferably less than 1%, more preferrably lessthan about 0.5% and most preferrably less than about 0.1% w/w (% ofsertraline hydrochloride Form I/sertraline hydrochloride).

The present invention also provides industrial scale processes (as wellas on the lab scale) for crystallizing a highly pure and/or stablesertraline hydrochloride Form II. By controlling the process andengineering parameters, sertraline hydrochloride may be crystallized inpure Form II on a consistent basis, even on an industrial scale.

Sertraline hydrochloride Form II of the present invention is produced bycontacting sertraline base in a suitable solvent with hydrogen chloridegas at a temperature range of about 30° C. to about 60° C., morepreferably at a temperature of from about 30° C. to about 50° C., evenmore preferably of about 30° C. to about 45° C., and most preferably ofabout 40° C. to about 45° C. Salts, such as sertraline mandelate mayalso be used as a starting material. A solution or a slurry may be usedwith the process of the present invention, though the base is highlysoluble in solvents such as n-butanol, making use of a solutionpreferable with the base.

Suitable solvents are those that allow for crystallization of sertralinehydrochloride Form II substantially free of sertraline hydrochlorideForm I. Examples of such solvents for preparation of Form II aredisclosed in U.S. Pat. Nos. 6,495,721 and 6,500,987, incorporated hereinby reference. Examples of such solvents include cyclohexane,isopropanol, n-propanol, 2-butanol, t-butanol, i-butanol, n-butanol(also known as 1-butanol), ethyl acetate, acetone, hexane,t-butyl-methyl ether, DMF, and mixtures thereof, particularly mixturesof n-butanol and DMF. From the above C₃ to C₄ alcohols, a preferredalcohol is n-butanol.

A process criteria for crystallization of sertraline hydrochloride pureForm II is the stability of the temperature during crystal formation ofpure Form II. Once a desired temperature is achieved, the temperature issubstantially maintained, i.e. within about ±5° C. in the specifiedrange (See e.g. Example 5). The ±5° C. allowance does not take theprocess out of the recited temperature range (See e.g. Example 5).

The process is carried out by adding hydrogen chloride gas to thesolution. Preferably, the gas flow is relatively fast, but a gas flowthat is too fast may cause operational problems. One problem is rapidprecipitation, which may cause difficulty in stirring. Chemical purityor polymorphic purity may also be adversely affected by a very fast gasflow.

The optimal amount of gas flow is dependent on the scale of the process.Preferably, the gas flow is of about 4 to about 6 grams of gaseoushydrogen chloride per hour per about 25 grams of sertraline base. Basedon this guidance, one of skill in the art would appreciate the properamount of gas flow when sertraline mandelate or another salt is used asa starting material.

In a laboratory scale (about 1 liter reactor) or production (industrial)scale (about 100 to about 630 liter reactors (i.e. a batch volume inthis size range is prepared; The batch volume for industrial scale maybe smaller, for example at least about 5/10 liters, which would giveproduct of about at least about 0.5/1 Kg respectively), the duration ofthe gas flow is preferably less than about 2 hours, more preferablyabout 1 hour. When the gas flow lasts for long durations, traces ofsertraline hydrochloride Form I inconsistently appear in small amounts(2-3% weight of sertraline hydrochloride Form I to sertralinehydrochloride). The gas flow is preferably for the duration of about ½hour to about 2 hours, more preferably of about ¾ hour to about 1¼ hour,and most preferably for about 1 hour. One of skill in the artappreciates that the optimal duration of the gas flow and the flow rateare dependent on the specifics of a bubbling process, such as the sizeof the bubbles.

The pH of the resulting slurry may be used to monitor the gas flow. Thegas flow is preferably stopped when reaching a pH of less than about1.0, more preferably when reaching a pH of at least about 0.5.

The substantially pure Form II may the be recovered from the slurry bytechniques well known in the art. In a particularly preferredembodiment, sertraline hydrochloride Form II is recovered by filtration.The temperature during filtration is preferably maintained from about30° C. to about 60° C., more preferably about 30° C. to about 50° C.,even more preferably from about 30° C./35° C. to about 45° C. and mostpreferably at a temperature of from about 40° C. to about 45° C. (aboutthe same range as the HCl addition step). The temperature is preferablythe same as that during the HCl addition, and more preferably thetemperature is kept substantially constant from the beginning of the HCladdition to the end of the filtration step. (See e.g. Example 5)

Sertraline hydrochloride Form II is kinetically stable when crystallizedas a highly pure sertraline hydrochloride Form II. The highly puresertraline hydrochloride Form II is stable during storage under stressconditions for at least about 2 weeks, more preferably for at leastabout 1-2 months, even more preferably for at least about 3 months andmost preferrably for at least about 6 months. In contrast, sertralinehydrochloride Form II that contains trace amounts of sertralinehydrochloride Form I (at least about 1% w/w of sertraline hydrochlorideForm I/sertraline hydrochloride) is not stable during storage under suchstress condition.

Without being bound by theory, it is believed that the level of puritypresently achieved in the highly pure sertraline hydrochloride Form IIimparts the polymorph with stability. It is believed that an unstablecomposition of sertraline hydrochloride Form II contains trace amountsof sertraline hydrochloride Form I, the presence of which facilitatesthe conversion of sertraline hydrochloride Form II to sertralinehydrochloride Form I, perhaps by providing a seed for crystallization.

The present invention also provides a pharmaceutical formulation,particularly oral dosage forms such as tablets containing fine crystalsof highly pure sertraline hydrochloride Form II. The active ingredientof the formulation, sertraline hydrochloride Form II, does notsubstantially convert into sertraline hydrochloride Form I. Hence it ispossible to formulate unit dosages such as tablets that are stableduring storage.

Storage of a tablet containing highly pure sertraline hydrochloride FormII at about 40° C. and about 75% relative humidity, for at least about1-2 weeks, more preferably from about 1-2 months and most preferably forat least about 3-4 months does not show any significant conversion toother polymorphic forms of sertraline hydrochloride, especially thestable Form I. Preferably, less than about 5%, more preferably, lessthan about 3% and most preferably, less than about 1% of the sertralinehydrochloride Form II in a tablet converts to polymorphic Form I ofsertraline hydrochloride following storage of the tablet. The detectionof sertraline hydrochloride Form I in a pharmaceutical formulation, tothe extent of about 1% w/w (% of sertraline hydrochloride FormI/sertraline hydrochloride), may be accomplished by use of x-ray powderdiffraction.

As in bulk sertraline hydrochloride Form II, the X-ray powderdiffraction pattern of pure sertraline hydrochloride tablet does notshow a substantial polymorphic change to Form I.

Pharmaceutical compositions of the present invention contain highly puresertraline hydrochloride Form II. In addition to the activeingredient(s), the pharmaceutical compositions of the present inventionmay contain one or more excipients. Excipients are added to thecomposition for a variety of purposes.

Diluents increase the bulk of a solid pharmaceutical composition, andmay make a pharmaceutical dosage form containing the composition easierfor the patient and care giver to handle. Diluents for solidcompositions include, for example, microcrystalline cellulose (e.g.Avicel®), microfine cellulose, lactose, starch, pregelatinized starch,calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose,dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin,magnesium carbonate, magnesium oxide, maltodextrin, mannitol,polymethacrylates (e.g. Eudragit®), potassium chloride, powderedcellulose, sodium chloride, sorbitol and talc.

Solid pharmaceutical compositions that are compacted into a dosage form,such as a tablet, may include excipients whose functions include helpingto bind the active ingredient and other excipients together aftercompression. Binders for solid pharmaceutical compositions includeacacia, alginic acid, carbomer (e.g. carbopol), carboxymethylcellulosesodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenatedvegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g.Klucel®), hydroxypropyl methyl cellulose (e.g. Methocel®), liquidglucose, magnesium aluminum silicate, maltodextrin, methylcellulose,polymethacrylates, povidone (e.g. Kollidon®, Plasdone®), pregelatinizedstarch, sodium alginate and starch.

The dissolution rate of a compacted solid pharmaceutical composition inthe patient's stomach may be increased by the addition of a disintegrantto the composition. Disintegrants include alginic acid,carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g.Ac-Di-Sol®, Primellose®), colloidal silicon dioxide, croscarmellosesodium, crospovidone (e.g. Kollidon®, Polyplasdone®), guar gum,magnesium aluminum silicate, methyl cellulose, microcrystallinecellulose, polacrilin potassium, powdered cellulose, pregelatinizedstarch, sodium alginate, sodium starch glycolate (e.g. Explotab®) andstarch.

Glidants may be added to improve the flowability of a non-compactedsolid composition and to improve the accuracy of dosing. Excipients thatmay function as glidants include colloidal silicon dioxide, magnesiumtrisilicate, powdered cellulose, starch, talc and tribasic calciumphosphate.

When a dosage form such as a tablet is made by the compaction of apowdered composition, the composition is subjected to pressure from apunch and dye. Some excipients and active ingredients have a tendency toadhere to the surfaces of the punch and dye, which may cause the productto have pitting and other surface irregularities. A lubricant may beadded to the composition to reduce adhesion and ease the release of theproduct from the dye. Lubricants include magnesium stearate, calciumstearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenatedcastor oil, hydrogenated vegetable oil, mineral oil, polyethyleneglycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate,stearic acid, talc and zinc stearate.

Flavoring agents and flavor enhancers make the dosage form morepalatable to the patient. Common flavoring agents and flavor enhancersfor pharmaceutical products that may be included in the composition ofthe present invention include maltol, vanillin, ethyl vanillin, menthol,citric acid, fumaric acid, ethyl maltol and tartaric acid.

Solid and liquid compositions may also be dyed using anypharmaceutically acceptable colorant to improve their appearance and/orfacilitate patient identification of the product and unit dosage level.

In liquid pharmaceutical compositions of the present invention,sertraline hydrochloride and any other solid excipients are dissolved orsuspended in a liquid carrier such as water, vegetable oil, alcohol,polyethylene glycol, propylene glycol or glycerin.

Liquid pharmaceutical compositions may contain emulsifying agents todisperse uniformly throughout the composition an active ingredient orother excipient that is not soluble in the liquid carrier. Emulsifyingagents that may be useful in liquid compositions of the presentinvention include, for example, gelatin, egg yolk, casein, cholesterol,acacia, tragacanth, chondrus, pectin, methyl cellulose, carbomer,cetostearyl alcohol and cetyl alcohol.

Liquid pharmaceutical compositions of the present invention may alsocontain a viscosity enhancing agent to improve the mouth-feel of theproduct and/or coat the lining of the gastrointestinal tract. Suchagents include acacia, alginic acid bentonite, carbomer,carboxymethylcellulose calcium or sodium, cetostearyl alcohol, methylcellulose, ethylcellulose, gelatin guar gum, hydroxyethyl cellulose,hydroxypropyl cellulose, hydroxypropyl methyl cellulose, maltodextrin,polyvinyl alcohol, povidone, propylene carbonate, propylene glycolalginate, sodium alginate, sodium starch glycolate, starch tragacanthand xanthan gum.

Sweetening agents such as sorbitol, saccharin, sodium saccharin,sucrose, aspartame, fructose, mannitol and invert sugar may be added toimprove the taste.

Preservatives and chelating agents such as alcohol, sodium benzoate,butylated hydroxy toluene, butylated hydroxyanisole and ethylenediaminetetraacetic acid may be added at levels safe for ingestion to improvestorage stability.

According to the present invention, a liquid composition may alsocontain a buffer such as guconic acid, lactic acid, citric acid oracetic acid, sodium guconate, sodium lactate, sodium citrate or sodiumacetate.

Selection of excipients and the amounts used may be readily determinedby the formulation scientist based upon experience and consideration ofstandard procedures and reference works in the field.

The solid compositions of the present invention include powders,granulates, aggregates and compacted compositions. The dosages includedosages suitable for oral, buccal, rectal, parenteral (includingsubcutaneous, intramuscular, and intravenous), inhalant and ophthalmicadministration. Although the most suitable administration in any givencase will depend on the nature and severity of the condition beingtreated, the most preferred route of the present invention is oral. Thedosages may be conveniently presented in unit dosage form and preparedby any of the methods well-known in the pharmaceutical arts.

Dosage forms include solid dosage forms like tablets, powders, capsules,suppositories, sachets, troches and losenges, as well as liquid syrups,suspensions and elixirs.

The dosage form of the present invention may be a capsule containing thecomposition, preferably a powdered or granulated solid composition ofthe invention, within either a hard or soft shell. The shell may be madefrom gelatin and optionally contain a plasticizer such as glycerin andsorbitol, and an opacifying agent or colorant.

The active ingredient and excipients may be formulated into compositionsand dosage forms according to methods known in the art.

A composition for tableting or capsule filling may be prepared by wetgranulation. In wet granulation, some or all of the active ingredientsand excipients in powder form are blended and then further mixed in thepresence of a liquid, typically water, that causes the powders to clumpinto granules. The granulate is screened and/or milled, dried and thenscreened and/or milled to the desired particle size. The granulate maythen be tableted, or other excipients may be added prior to tableting,such as a glidant and/or a lubricant.

A tableting composition may be prepared conventionally by dry blending.For example, the blended composition of the actives and excipients maybe compacted into a slug or a sheet and then comminuted into compactedgranules. The compacted granules may subsequently be compressed into atablet.

As an alternative to dry granulation, a blended composition may becompressed directly into a compacted dosage form using directcompression techniques. Direct compression produces a more uniformtablet without granules. Excipients that are particularly well suitedfor direct compression tableting include microcrystalline cellulose,spray dried lactose, dicalcium phosphate dihydrate and colloidal silica.The proper use of these and other excipients in direct compressiontableting is known to those in the art with experience and skill inparticular formulation challenges of direct compression tableting.

A capsule filling of the present invention may comprise any of theaforementioned blends and granulates that were described with referenceto tableting, however, they are not subjected to a final tableting step.

Preferably, the pharmaceutical formulations of the present invention aresolid dosage forms in the form of a tablet for the oral administrationof sertraline hydrochloride. The highly pure sertraline hydrochlorideForm II used for preparing a tablet may be in the form of fine crystals.Preferably, the fine crystals have a particle size distribution suchthat 100% of the particles are below 200 microns, more preferably below100 microns and most preferably below about 50 microns.

Methods known in the art, as described above, may be used to preparetablets of sertraline hydrochloride Form II. Highly pure sertralinehydrochloride Form II tablets may be prepared for instance by mixing theactive ingredient, sertraline hydrochloride pure Form II, with acombination of excipients including, lactose, povidone, microcrystallinecellulose and croscarmellose sodium. Purified water may be added to thepowder mixture of sertraline modification II and excipients. The mixturemay be then dried until only trace amounts of fluid remain in thegranulate as residual moisture. Preferably, the mixture is dried to aloss on drying (“LOD”) no more than (“NMT”) about 0.5 to about 3%. Thegranulate may be then sieved, and magnesium stearate may be added to themilled granulate. The final blend of sertraline modification II,excipients and magnesium stearate is compressed into tablets and may befilm coated, preferably with Opadry® (Colorcon, Westpoint Pa.).According to Colorcon, Opadry® is a one-step customized coating systemthat combines polymer, plasticizer, and if desired, a pigment in dryconcentrate. Table 1 shows suitable ranges of active ingredients andexcipients (weight %) and the preferred amounts for the presentpharmaceutical formulations. TABLE 1 Range of % composition Preferred %Material (w/w) composition Function High purity sertraline    20-35%28.0 Active ingredient modification II Lactose Monohydrate 25-40 32.0Filler Croscarmellose  5-12 10.0 Disintegrant Sodium NF Povidone USP 1-32.4 Binder (PVP K-30) Microcrystalline 20-40 26.6 Filler and CelluloseNF disintegrant (Avicel PH 102) Purified water USP — — Granulationprocessing solvent Magnesium Stearate 0.5-2.5 1.0 Lubricant NF* Granulation processing solvent only (dried to achieve moisture contentof LOD-NMT about 0.5-1.5%).

In accordance with the present invention, the pharmaceuticalformulations of the present invention are useful for inhibiting there-uptake of serotonin, thus resulting in an increased level ofserotonin. An increased level of serotonin alleviates symptoms ofpsychiatric disorders such as depression. The oral pharmaceutical dosageforms of the present invention preferably contain of about 20 mg toabout 100 mg of the base equivalent of sertraline hydrochloride, withabout 25 mg, about 50 mg and about 100 mg tablets being preferred.

Instrumentation Used:

X-Ray powder diffraction data was obtained by using a SCINTAG powderX-Ray diffractometer model X'TRA equipped with a solid state detector.Copper radiation of 1.5418 Å was used. The diffractometer was equippedwith a round aluminum sample holder with round zero background quartzplate having a cavity of 25(diameter)*0.5(depth) mm.

EXAMPLES Example 1

Stability of bulk sertraline hydrochloride Form II and tablet PolymorphContent Polymorph Content of sertraline hydrochloride of bulk sertralineLength of in tablet hydrochloride Storage 40° C., 75% RH 40° C., 75% RHPolymorphic Form Polymorphic Form detected (I or II) detected (I or II)II > I(<1%) II > I(<1%) t = 0 II > I(<3%) II > I(<1%) 1 month II >I(<3%) II > I(2%) 2 months II > I(3%) II > I(2%) 3 months — II > I(4%) 4months

Example 2

Stability of highly pure bulk sertraline hydrochloride Form II andtablet Polymorph Content Polymorph Content of sertraline hydrochlorideof bulk sertraline Length of in tablet hydrochloride Storage 40° C., 75%RH 40° C., 75% RH Polymorphic Form Polymorphic Form detected (I or II)detected (I or II) II* II* t = 0 II II 1 month II II 2 months — — 3months — II 6 months*The presence of Form I was below the detection level in Examples 2-4.The detection level for the tablet was less than about 1% weight ofsertraline hydrochloride Form I to the weight of sertralinehydrochloride, and in the bulk less than about 0.1%.

Example 3

Stability of highly pure bulk sertraline hydrochloride Form II andtablet Polymorph Content Polymorph Content of sertraline hydrochlorideof bulk sertraline Length of in tablet hydrochloride Storage 40° C., 75%RH 40° C., 75% RH Polymorphic Form Polymorphic Form detected (I or II)detected (I or II) II II t = 0 II II 1 month II II 2 months — — 3 months— II 6 months

Example 4

Stability of highly pure bulk sertraline hydrochloride Form II andtablet Polymorph Content Polymorph Content of sertraline hydrochlorideof bulk sertraline Length of in tablet hydrochloride Storage 40° C., 75%RH 40° C., 75% RH Polymorphic Form Polymorphic Form detected (I or II)detected (I or II) II II t = 0 II II 1 month II II 2 months — — 3 months— II 6 months

Example 5

Preparation of Pure Sertraline Hydrochloride Form II in Lot (Industrial)Scale

Sertraline base (27 kg) obtained directly from synthesis was dissolvedin 105 kg of n-butanol. The solution was treated for 1 hour with 1 kgcarbon at 40° C.-45° C., filtered and washed with 25 kg n-butanol. Thesolution was reheated to 40° C.-45° C. and the achieved temperature waskept constant during the gas flow and filtration. Hydrogen chloride gaswas added at the rate of 4.5-5 kg/hr for the duration of 1 hour until pH0.5 or less was reached. Immediately after, the slurry was filtered at40° C.-45° C. The cake was washed with 25 kg of n-butanol, and dried forabout 4 hours at 80° C. The yield was 70% (21.2 Kg).

Example 6

Preparation of Pure Sertraline Hydrochloride Form II in Lab Scale

Sertraline base (26 g) obtained directly from the synthesis wasdissolved in n-butanol (6 volumes) (140 ml). The solution was treatedfor 1 hour with 1.1 g carbon at 40° C.-45° C., filtered and washed with12 cc n-butanol. The solution was reheated to 40° C.-45° C. and thetemperature achieved was kept constant during the gas flow andfiltration. Hydrogen chloride gas was added at the rate of 4-6 g/hr forthe duration of 1 hour until pH 0.5 or less was reached. Immediatelyafter, the slurry was filtered at 40° C.-45° C. The cake was washed with30 ml of n-butanol, and dried for about 4 hours at 80° C.

Example 7

Preparation of Sertraline Hydrochloride in n-BuOH at 70° C.

Sertraline base (30 g) in n-BuOH (240 ml) was heated to 50° C. HCl (g)was bubbled to the solution and the temperature rose to 70° C.; when thepH reached 1.5, precipitation was observed (the temperature was 68° C.More HCl was purged through the slurry (the temperature was 65° C.).After the pH reached 0.5, the mixture was cooled to room temperature anda solid was filtrered and washed with n-BuOH. After drying, a mixture ofsertraline hydrochloride form II and form I was obtained (26.41 g).

Example 8

Preparation of Sertraline Hydrochloride in n-BuOH by Filtration at 10°C.

Sertraline base (30 g) was dissolved in n-BuOH(240 ml) and HCl(g) wasbubbled through the solution. The temperature rose to 45° C. Thereaction mixture turned to a gelly like mixture, which then became aslurry. The slurry was cooled to 10° C. and a solid was filtered, andwashed with n-BuOH. After drying, a mixture of sertraline hydrochlorideform II and I was obtained (25.9 g).

Example 9

Preparation of Sertraline Hydrochloride Form II in n-BuOH fromSertraline Mandelate

Sertraline mandelate (20 g) in n-BuOH (400 ml) was heated to 60° C. Aslurry was obtained. HCl (g) was bubbled through the mixture andcomplete dissolution was observed. When the solution pH was ˜0.5, thesolution was cooled and seeded with sertraline hydrochloride Form II.The reaction mixture was srirred at room temperature over night and asolid was filtered and washed with n-BuOH. The solid was dried to affordsertraline hydrochloride Form II (7.21 g).

Having thus described the invention with reference to particularpreferred embodiments and illustrative examples, those in the art mayappreciate modifications to the invention as described and illustratedthat do not depart from the spirit and scope of the invention asdisclosed in the specification. The Examples are set forth to aid inunderstanding the invention but are not intended to, and should not beconstrued to, limit its scope in any way. The examples do not includedetailed descriptions of conventional methods. Such methods are wellknown to those of ordinary skill in the art and are described innumerous publications. Polymorphism in Pharmaceutical Solids, Drugs andthe Pharmaceutical Sciences, Volume 95 may be used as a guidance. Allreferences and priority documents mentioned herein are incorporated byreference in their entirety.

1-39. (canceled)
 40. A process for the preparation of sertralinehydrochloride polymorphic form II, wherein a solution of sertraline freeamine is seeded with some crystals of polymorphic form II and hydrogenchloride is added.
 41. The process of claim 40, wherein hydrogenchloride is added as a gas.
 42. A process of claim 40, wherein thesolution of sertraline free amine is seeded with some crystals ofpolymorphic form II and subsequently hydrogen chloride is added.
 43. Theprocess of claim 42, wherein hydrogen chloride is added as a gas.
 44. Aprocess of claim 40, wherein hydrogen chloride is added to the solutionof sertraline free amine and subsequently the solution is seeded withsome crystals of polymorphic form II.
 45. The process of claim 44,wherein hydrogen chloride is added as a gas.